1. Field of the Invention
The present invention relates to a drug complex of a drug having a hydroxyl group, wherein the drug complex is capable of controlling the rate of the release of the drug therefrom in blood when administered to a living body. The present invention also relates to a novel polysaccharide-taxane complex which is capable of not only obviating the defect (poor water-solubility) of a drug, for example, a taxane compound which is useful as an antitumor drug, but also delaying the disappearance of the taxane compound from blood and also enhancing the transferability of the taxane compound to tumor tissues.
2. Prior Art
Paclitaxel (tradename: Taxol; manufactured and sold by Bristol-Myers Squibb, U.S.A.) is a naturally occurring product, which is extracted from the bark of a taxaceous tree, Taxus brevifolia, native to Pacific-rim countries, and has been confirmed to have excellent antitumor activities by assays using animal models. In recent studies, it has been reported that the antitumor activities of paclitaxel is due to a specific mechanism involving the induction of abnormal polymerization of tubulin and the inhibition of mitosis. Further, in recent years, promising results have been obtained in the studies with respect to the antitumor activities of paclitaxel against various types of tumors, such as oophoroma, mastocarcinoma, carcinoma of colon and rectum, and lung cancer. A semi-synthesized homologue of paclitaxel, called docetaxel (tradename: Taxotere; manufactured and sold by Rhxc3x4ne-Poulenc Rorer Pharmaceuticals Limited, U.S.A./France), has also been found to have good antitumor activities.
One of the defects of taxane compounds, a representative example of which is paclitaxel, is poor solubility in water. Therefore, paclitaxel needs to be formulated into a pharmaceutical composition by use of a non-aqueous adjuvant for dissolving medicines. One of the dissolving adjuvants, which are currently used, is Cremophor EL (manufactured and sold by Sigma, U.S.A.). However, Cremophor EL itself may cause undesirable adverse side effects, such as anaphylaxis in human. For that reason, a lot of researches have been made with respect to water-soluble derivatives of paclitaxel. For example, the technique of using phosphonooxymethyl ether derivatives of taxane compounds [Unexamined Japanese Patent Application Laid-Open Specification (Japanese Kokai) No. 7-149779] and the technique of using carbonate type and ester type pro-drugs of taxane compounds having a leaving moiety which can be removed under basic conditions [Nature, 365, 464-466 (1993)] are known. However, satisfactory techniques have not yet been developed with respect to prodrugs of taxane compounds.
In the techniques to improve various defects of a drug by chemically modifying the molecular structure of the drug, the effectiveness of the prodrug comprising a drug having bonded thereto a leaving moiety depends heavily on the selection of the mode of a bonding between the drug and the leaving moiety [see xe2x80x9cDoraggu Deribarii Sisutemuxe2x80x9d (Drug Delivery System), edited by Hitoshi Sezaki and published by Nankodo, Japan]. In general, when it is intended to restore a drug from a prodrug by utilizing an enzymatic reaction, the types of enzymes distributed broadly in a living body, such as an esterase, an amidase and a carbamidase, will be determining factors for selecting the appropriate bonding mode. Therefore, when the drug has a hydroxyl group, the bonding mode is frequently selected among a carboxylic ester bond, a phosphoric ester bond and an acyloxymethyl ether bond, and when the drug has a carboxyl group, the bonding mode is frequently selected between an ester and an amide bond.
On the other hand, in general, high molecular weight compounds exhibit various unique properties and functions and, therefore, interact with a living body in manners which are largely different from the manners in which low molecular weight compounds interact with a living body. Therefore, a large number of attempts have been made, in which a drug having a low molecular weight is bonded to a high molecular weight compound as a leaving moiety to thereby produce a prodrug and the prodrug is used so as to control the behavior of the drug in a living body and the interactions between the drug and cells. Also in this case, the selection of the mode of a bonding between the drug and the high molecular weight compound is an important factor of determining the effectiveness of the prodrug. Usually, in a prodrug comprising a drug having bonded thereto a leaving moiety, the functional group of the drug is directly bonded to the functional group of the leaving moiety. It is still rare that a prodrug is constructed such that the drug is bonded to the leaving moiety through a spacer.
With respect to examples of such prodrugs comprising a drug, a spacer and a leaving moiety, although the number of examples thereof is small, there can be mentioned an example in which a carboxymethylated dextran (carboxymethyldextran), which is a high molecular-weight polysaccharide, is used as a carrier. In this example of prodrug, doxorubicin having an amino group in the structure thereof is used as a drug, wherein a carboxymethyl dextran is introduced into the amino group of doxorubicin through the spacer (see, International Application Publication No. WO 94/19376). As mentioned above, doxorubicin has an amino group in the structure thereof. In this technique, a peptide is used as a spacer. Therefore, each of the mode of the bonding formed between the amino group of the spacer and the carboxyl group of the carboxymethyldextran and the mode of the bonding formed between the carboxyl group of the spacer and the amino group of the drug is an amide bond. However, an amide bond is extremely stable in blood and, therefore, the rate of the release of the drug from the drug complex (prodrug) is very low in blood. Further, it is noted that, in this WO publication, there is no description with respect to the release of a drug having a hydroxyl group.
As examples of prodrugs containing a synthetic polymer as a carrier, there can be mentioned prodrugs comprising doxorubicin as a drug, in which a high molecular weight compound (HPMA) (which is a product of copolymerization of a plurality of hydroxypropyl methacrylamide derivatives) is bonded to doxorubicin at the amino group thereof through a peptide as a spacer [see, J. Contr. Rel., 10, 51-63 (1989), J. Contr. Rel., 19, 331-346 (1992), Eur. J. Cancer, 31A (suppl 5), S193 (1995)]. In these examples also, each of the mode of each of the bonding between the drug and the spacer and the mode of the bonding between the spacer and the carrier is an amide bond. Further, as mentioned above, the carrier is a synthetic polymer. Therefore, it is predicted that the carrier would not be degraded (metabolized) at all in a living body. As a result, when a drug complex (prodrug) containing the above-mentioned synthetic polymer as a carrier is administered to a living body, there is a danger of the accumulation of the toxicity and antigenicity of the carrier because the carrier stays as a foreign substance in a living body for a long period of time. Therefore, the molecular weight of the carrier should be controlled to a level such that the carrier is not accumulated in a living body, but can be excreted rapidly.
As another example of a prodrug containing, as a carrier, a synthetic polymer produced in substantially the same manner as mentioned above, there can be mentioned a prodrug comprising paclitaxel (a drug having hydroxyl groups) as a drug, in which a high molecular weight compound (HPMA) (which is a product of copolymerization of a plurality of hydroxypropylmethacrylamide derivatives) is bonded to the paclitaxel at least at one of the hydroxyl groups thereof through a peptide as a spacer (see, U.S. Pat. No. 5,362,831). In this case also, since the carrier is a synthetic polymer, it is predicted that the carrier would not be degraded at all in a living body. As a result, when a drug complex (prodrug) having the above-mentioned synthetic polymer as a carrier is administered to a living body, there is a danger of the accumulation of the toxicity and anti-genicity of the carrier because the carrier stays as a foreign substance in a living body for a long period of time. Therefore, the molecular weight of the carrier should be controlled to a level such that the carrier is not accumulated in a living body, but can be excreted rapidly.
Further, as still another example of a prodrug containing a synthetic polymer as a carrier, there can be mentioned a prodrug comprising paclitaxel (a drug having hydroxyl groups) as a drug, and a polyethylene glycol having introduced thereinto a carboxyl group (hereinafter, simply referred to as xe2x80x9cPEG-COOHxe2x80x9d), in which a PEG-COOH is bonded, at the carboxyl group thereof, directly to the paclitaxel at least at one of the hydroxyl groups thereof through an ester bond [see, Bioorganic and Medicinal Chemistry Letters, Vol. 4, No. 20, 2465-2470 (1994)]. In this case, the water-solubility of paclitaxel has been improved by bonding paclitaxel to a PEG-COOH so as to form a prodrug.
However, although the prodrug thus formed is stable in a buffer, the ester bond of the prodrug is likely to be rapidly cleaved in blood. Therefore, this prodrug (comprising a drug having bonded thereto a polymer by chemical modification) is still unsatisfactory for attaining the purpose of stably delivering the drug to a target site in a living body.
As apparent from the above, in the techniques of delivering a drug in the form of a prodrug comprising a carrier having bonded thereto a drug through a chemical bond, especially when the chemical bond is an ester bond, the rapid cleavage of an ester bond by an esterase or the like present is likely to occur in a living body. Therefore, the problems of the difficulty of the control of the rate of the release of a drug from a drug complex (prodrug) have not yet been fully solved.
In this situation, the present inventors have made extensive and intensive studies toward developing a drug complex which is capable of controlling the rate of the release of a drug therefrom, and which is obtained by introducing a spacer into the drug and then bonding the introduced spacer to a carrier.
As a result, it has unexpectedly been found that, when a drug complex of a drug having a hydroxyl group is constructed such that it comprises at least one a carrier having at least one carboxyl group, at least one spacer having at least one amino group and at least one carboxyl group, and at least one drug having a hydroxyl group, wherein the spacer is introduced to the drug through an ester bond formed between the hydroxyl group of the drug and the carboxyl group of the spacer, and wherein the spacer is bonded to the carrier through an amide bond formed between the amino group of the spacer and the carboxyl group of the carrier, the so constructed drug complex is capable of controlling the rate of the release of the drug from the drug complex.
It has also been found that a very effective control of the rate of the release of the drug from the drug complex can be achieved by appropriately selecting at least one spacer having a substituent X at the xcex1-position relative to the carboxyl group of the spacer, wherein the substituent X has a specific Es value.
It has also been found that, when a drug complex of a drug having a hydroxyl group is constructed such that it comprises at least one carrier having at least one carboxyl group, at least one spacer having at least one amino group and at least one carboxyl group and having a substituent X at the xcex1-position relative to the carboxyl group thereof, and at least one water-insoluble drug having a hydroxyl group, such as a taxane compound, wherein the spacer is introduced to the drug through an ester bond formed between the hydroxyl group of the drug and the carboxyl group of the spacer, wherein the spacer is bonded to the carrier through an amide bond formed between the amino group of the spacer and the carboxyl group of the carrier, and wherein the spacer is selected so that substituent X has a specific Es value, the so constructed drug complex is capable of not only controlling the rate of the release of the drug from the drug complex, but also improving the water-solubility of the drug, so that not only can the transferability of the drug to target tissues, such as tumor tissues, be enhanced, but also the exertion of the effect of the drug can be controlled.
Further, it has been found that, when the drug complex has a structure in which a taxane compound is used as the drug, a spacer is introduced into the 2xe2x80x2- or, 7-positioned hydroxyl group of the taxane compound through an ester bond, and a carboxyalkyldextran is used as the carrier, the so constructed drug complex is capable of not only extremely improving the water-solubility of the taxane compound, but also decreasing the rate of the disappearance of the taxane compound in blood, and increasing the transferability of the drug to tumor tissues, thereby enhancing the effect of the taxane compound.
Still further, it has been found that, when the drug complex has a structure in which at least one steroid having a primary hydroxyl group, such as beta-methasone or prednisolone, is used as the drug, at least one spacer (such as an amino acid) having a substituent X at the xcex1-position relative to the carboxyl group thereof, wherein the spacer is appropriately selected so that the substituent X has a specific Es value, is introduced into the primary hydroxyl group of the steroid through an ester bond, and a carboxyalkylmonosaccharide or an aliphatic carboxylic acid, such as acetic acid and propionic acid, is used as the carrier, the so constructed drug complex is capable of controlling the rate of the release of the steroid from the drug complex in a living body, whereas, in a compound (drug complex) prepared by directly bonding a carboxyalkylmonosaccharide as a carrier, [use of a carboxyalkylmonosaccharide as a carrier has been reported in Chem. Pharm. Bull., 42(10), 2090-2096(1994)], or an aliphatic carboxylic acid, such as acetic acid and propionic acid, as a carrier, to the primary hydroxyl group of the steroid, such as betamethasone or prednisolone, through an ester bond, the release of the steroid from the compound is disadvantageously rapid.
Furthermore, it has been found that, when the drug complex has a structure in which at least one paclitaxel having hydroxyl groups is used as the at least one drug, at least one spacer (such as an amino acid) having a substituent X at the xcex1-position relative to the carboxyl group thereof, wherein the spacer is appropriately selected so that the substituent X has a specific Es value, is introduced into one of the hydroxyl groups of the paclitaxel through an ester bond, and a PEG-COOH is used as the carrier, the so constructed drug complex is capable of controlling the rate of the release of paclitaxel from the drug complex in a living body, whereas, in a compound prepared by directly bonding PEG-COOH as a carrier to the hydroxyl group of a drug having hydroxyl groups through an ester bond in a conventional manner, the release of the drug from the compound is disadvantageously rapid in a plasma of rat or human, although the compound is so stable in a buffer that the-half-life of the above-mentioned compound in a buffer is 3 hours or more [see J. Med. Chem., 39, 1938-1940(1996)].
The present invention has been completed based on the above novel findings.
Accordingly, it is an object of the present invention to provide a drug complex of a drug which is capable of not only surely controlling the rate of the release of the drug from the drug complex, but also enhancing the transferability of the drug to the target tissues and the effectiveness of the drug.
It is another object of the present invention to provide a drug complex comprising a taxane compound as a drug, wherein the drug complex is not only capable of extremely improving the solubility of the taxane compound in water, but also surely controlling the rate of the release of taxane compound from the drug complex and enhancing the transferability of the taxane compound to the target tissues and the effectiveness of the taxane compound.
It is still another object of the present invention to provide a medicine, which comprises the above-mentioned drug complex.
The foregoing and other objects, features and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and appended claims taken in connection with the accompanying drawings.